| BackgroundThe stress hyperglycemia occurred in critical illness has been an independent riskfactor which is related with the mortality of patients, thus hyperglycemia control has beendoctors’ common sense in critical care medicine. However, it’s showed that regular doseof insulin usually can not control the stress hyperglycemia in critical illness. Recently,intensive insulin therapy was recommended to control hyperglycemia and showed brightprospect in decreasing mortality in ICU. To our disappointment that the hypoglycemiaaccident during this procedure limits the widespread use of intensive insulin therapy.Our team found that there was acute insulin resistance (AIR) following severe burnwhich is the primary reason for the difficulty of stress hyperglycemia control. Therefore,elucidation the mechanism of AIR and finding new ways to alleviate AIR in critical illness have already been urgent issues.Advanced glycation endproducts (AGEs) were found in diabetic patients whichparticipated in the damage of insulin sensitivity. AGEs recognize the transmembranereceptor (receptor for advanced glycation endproducts, RAGE) and initiate theintracellular signaling that disrupts celluar function. sRAGE, the extracellular ligandbinding domain of RAGE, soluble receptor for advanced glycation endproducts (sRAGE),blocks AGEs from binding to RAGE and disrupts the biological effect of AGEs. Recentstudies have showed that carboxymethyllysine (CML), a dominate AGEs in vivo,participats in myocardial ischemia/reperfusion and stroke. But the roles of AGEs in burninjury and AIR have not been reported. The treatment targeting AGEs is necessary toameliorate AIR and improve the prognosis of patients.Aims1. To investigate the mechanism of AIR following severe burn, especially the productionof the AGEs postburn and it’s role in AIR.2. To explore whether early insulin treatment decreases the level of AGEs, inhibits AIRand increases the survival rate postburn.MethodsYoung adult (180-200g) SD rats were subjected to40%burn area to build the severeburn model. PET/CT was used to determine the glucose uptake. IPGTT test was used toassess the glucose tolerance. H9C2cell were cultured to investigate the in vitro insulinsensitivity interrupted by AGEs. The tissue and cell proteins were extracted and westernblotting was used to evaluate pAkt/Akt, pGSK-3β/GSK-3β, and CML expression levels.sRAGE and CML in serum were detected by ELISA kit.Results1. Insulin sensitivity decreased at3h following severe burn evidenced byhyperglycemia (10.0±1.0mM vs.6.5±0.1mM. n=31/group, compared with sham,**P<0.01), inhibition insulin stimulated glucose uptake of heart and decreasedpAkt/Akt and pGSK-3β/GSK-3β in heart and skeletal muscle.2. The CML level increased at0.5h （14.61±0.65ng/ml vs.11.60±0.72ng/ml. n=6/group, compared with sham,*P<0.05）and reached a peak at1h (18.61±1.34ng/ml vs.10.32±0.94ng/ml. n=6/group, compared with sham,**P<0.01) followingsevere burn in serum as well as in skeletal muscle.3. Early exogenous sRAGE treatment (3μg/kg) decreased the CML peak at1h followingburn (12.64±0.69ng/ml vs.19.11±1.22ng/ml. n=6/group, compared with burngroup,**P<0.01), inhibited the hyperglycemia at3h (7.40±0.47mM vs.10.05±0.92mM. n=15, compared with burn,**P<0.01) and increased the pAkt/Akt in heart andskeletal muscle. IPGTT test showed that the glucose tolerance increased at3hpostburn compared with the vehicle treatment group.4. Insulin sensitivity was compromised in vivo2h after intravenous injectionMethylglyoxal (MG, an AGEs precursor) evidenced by decreased pAkt/Akt in heartand skeletal muscle. IPGTT test showed that the glucose tolerance was inhibited afterMG injection.5. Insulin sensitivity was compromised in vitro by CML-BSA treatment for1h in H9C2cell evidenced by decreased both basal (0.19±0.11vs.0.66±0.17. n=4, comparedwith control,**P<0.01) and insulin-stimulated Akt activation (0.40±0.12vs.1.70±0.29. n=4, compared with control,**P<0.01).6. Early insulin treatment after burn decreased the AGEs level at1h (9.34±0.90ng/mlvs.18.32±1.72ng/ml. n=6/group, compared with burn group,**P<0.01) andhyperglycemia within12h. IPGTT test showed that the glucose tolerance wasincreased by insulin treatment. These results showed that insulin alleviated AIR at3hby inhibiting AGEs production following severe burn.7. Early sRAGE or insulin treatment improved the survival rate of rats following severeburn (92%vs.71%,*P<0.05, n=27；95%vs.71%,*P<0.05, n=43).Conclusions1. Severe burn-induced acute insulin resistance (AIR) was mediated by elevatedproduction of advanced glycation endproducts (AGEs) at1h postburn.2. Early sRAGE or insulin treatment after burn decreased AGEs level, ameliorated AIRand increased survival rate following burn. |
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